Development of a sustainable reaction sequence for the synthesis of 9,11-secosterols and its application in the synthesis of aplysiasecosterols and pinnigorgiols using a terminated (vinylogous) ketol rearrangement cascade

• Applicant: Professor Dr. Philipp Heretsch
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396114738

The synthesis of even simple 9,11-secosterols frequently relies on the use of toxic heavy metals, i.e. mercury, osmium, and lead, typically in greater than stoichiometric quantities. In the last two years, the aplysiasecosterols and pinnigorgiols (oxygen-rich tricyclo[5,2,1,1]decanes) were isolated. As a biosynthetic hypothesis, a cascade of (vinylogous) ketol rearrangements of 9,11-secosterols was proposed. Biologically, the aplysiasecosterols and pinnigorgiols, as well as their possible biosynthetic precursors, the pinnisterols, possess several interesting bioactivities. Aplysiasecosterol, for example, is a selective inhibitor of certain human myelogenous leukemia cell lines.The aim of this project is thus, to establish a sustainable, and general access to 9,11-secosterols, that does not rely on the use heavy metals. Preliminary work for this project has already led to one example where this prerequisite ilphas fulfilled. Building upon these results, we will next apply our published work on the synthesis of strophasterol (a 14,15-secosterol) to the synthesis of 9,11-secosterols and use both, the anionic rearrangement of a-chloro-gamma-hydroxy-delta-keto-enones as well as the synthesis of meta-endoperoxide peroxides from 5,8-steroidal dienes. With a route to 9,11-secosterols in hands, the realization of the (vinylogous) ketol rearrangement cascade will then be attempted. This will also shed some light on the biosynthetic rationale of these natural products. Eventually, studies in the anticipated natural products from the corresponding pinnisterols and irciniasecosterols will be conducted.

• DFG Programme: Research Grants